Abstract The objective of this study is to develop a novel and effective therapeutic approach for the treatment of melanoma, specifically using hyperthermia to modulate the delivery of the FDA approved anticancer drug Abraxane (human serum albumin (HSA) based paclitaxel-nanoparticle) to tumors. Approximately 76,000 individuals will be diagnosed with melanoma, and about 9,000 will die as a result of the disease this year in the United States. Even though there are many options for the treatment of melanoma, the mortality rate is still high. The high mortality rate partially reflects a lack of effective treatment methods, particularly for patients with late stage disease. In a study, we discovered that HSA levels increased more than 10-fold in melanoma cells heated at 41oC for less than 1 hour (flow cytometry analysis). In contrast, the levels of HSA did not change in normal untransformed human fibroblasts after the same heat treatment. Therefore, we hypothesize that mild/moderate hyperthermia could efficiently modulate Abraxane delivery to tumors in vivo and enhance therapeutic efficacy in the treatment of melanoma. In the proposed study, we will label Abraxane with near infrared (NIR) dye and use both local and whole body hyperthermia to modulate delivery of Abraxane to orthotopic melanoma xenografts and metastatic melanoma tumors in vivo. The working system of orthotopic melanoma treated with local hyperthermia will allow us to observe accumulation of Abraxane-NIR conjugate in xenograft tumors and optimize the heat treatment regimen for maximal delivery of the Abraxane-NIR conjugate to tumors by comparing mean values of fluorescence intensity among tumors heated at different temperatures and durations. The mice with lung metastatic melanoma, which represent patients with late stage disease, will be treated with whole body hyperthermia. This will allow us to assess the feasibility of using whole body hyperthermia to modulate Abraxane delivery to metastatic tumors. Note that hyperthermia has already been used to improve blood circulation, increase tumor cell membrane permeability for anticancer chemical diffusion passively, oxygenate hypoxia tumor cells, and inhibit DNA repair to make tumor cells more susceptible to chemo/radiotherapy. The novelty of this application is: 1) the discovery of additional significant increase in the amount of HSA in tumor cells after heat treatment; 2) actively modulating the delivery of anticancer drug Abraxane to primary and metastatic melanomas using local and whole body hyperthermia in vivo; 3) conjugation of Abraxane with NIR dye to observe the anticancer drug biodistribution and kinetic changes in vivo. Results from this study may lead to rapid clinical trials because both hyperthermia and the anticancer drug Abraxane are already in use, albeit individually at present. Successful completion of the proposed study may significantly reduce mortality and improve quality of life for melanoma patients.